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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptNIH Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
J Perinat Med. Author manuscript; available in PMC Apr 13, 2012.
Published in final edited form as:
PMCID: PMC3325506
NIHMSID: NIHMS268257

Microbial invasion of the amniotic cavity in preeclampsia as assessed by cultivation and sequence-based methods

Abstract

Objective

Infection has been implicated in the pathogenesis of preeclampsia, yet the association between microbial invasion of the amniotic cavity (MIAC) and preeclampsia has not been determined. The aim of this study was to determine the prevalence, and microbial diversity associated with MIAC, as well as the nature of the host response to MIAC in patients with preeclampsia.

Method of study

Amniotic fluid (AF) from 62 subjects with preeclampsia, not in labor, was analyzed with both cultivation and molecular methods. Broad-range and group-specific PCR assays targeting small subunit ribosomal DNA, or other gene sequences, from bacteria, fungi and archaea were used. Results were correlated with measurements of host inflammatory response, including AF white blood cell count and AF concentrations of glucose, interleukin-6 (IL-6) and MMP-8.

Results

1) The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation techniques, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods; 2) among the six patients diagnosed with MIAC, three had a positive PCR for Sneathia/Leptotrichia spp.; and 3) patients with MIAC were more likely to have evidence of an inflammatory response in the amniotic cavity than those without MIAC, as determined by a higher median AF IL-6 [1.65 ng/mL interquartile range (IQR): 0.35–4.62 vs. 0.22 ng/mL IQR: 0.12–0.51; P=0.002).

Conclusion

The prevalence of MIAC in preeclampsia is low, suggesting that intra-amniotic infection plays only a limited role in preeclampsia. However, the unexpectedly high number of positive AF specimens for Sneathia/Leptotrichia warrants further investigation.

Keywords: IL-6, intra-amniotic infection, intra-amniotic inflammation, PCR, preeclampsia, pregnancy, 16S rRNA, Sneathia/Leptotrichia spp, Ureaplasma urealyticum

Introduction

Preeclampsia, one of the “great obstetrical syndromes” [32, 100, 101], is a major cause of maternal and perinatal morbidity and mortality [30, 69, 74, 85, 114, 118]. Preeclampsia has been associated with several mechanisms of disease including defective spiral artery remodeling [15, 39, 55], endothelial cell dysfunction [13, 23, 51, 58, 84, 90, 95, 98, 112, 125], an anti-angiogenic state [4, 17, 1921, 26, 37, 38, 40, 47, 57, 5961, 6468, 70, 73, 75, 78, 91, 99, 105, 115, 121, 122, 127, 130133, 135, 146], an exaggerated intravascular inflammatory response [7, 18, 22, 45, 48, 71, 72, 76, 77, 93, 94, 97, 109, 119, 120, 128, 129, 134, 142], oxidative stress [28, 52, 82, 83, 138] and a predominantly T helper (Th1)-biased immune response [6, 10, 25, 27, 35, 62, 79, 110, 123, 126, 137, 139].

Several lines of evidence support a role for infection in preeclampsia: 1) women with asymptomatic bacteriuria are more likely to develop preeclampsia than those with a negative urine culture [136]. Indeed, urinary tract infection in pregnancy is associated with an odds ratio (OR) of 2.5 [95% confidence interval (CI) 1.3–5.0] for the development of preeclampsia. This rate is even higher among primigravidae [OR 5.5 (95% CI 2.9–9.7)] [81]; 2) a HELLP syndrome-like state can be induced by stimulation of the celiac ganglion with lipopolysaccharide (LPS) in non-pregnant rats [53]; 3) exposure of pregnant rats to low doses of endotoxin in early pregnancy leads to the development of preeclampsia [41, 42, 111]; 4) the presence of periodontal disease at <26 weeks of gestation increases the risk for subsequent preeclampsia [OR 2.3 (95% CI 1.0–5.2)] [9]; 5) case reports have linked recurrent eclampsia with chronic pyelonephritis [108]; and 6) preeclampsia has been associated with chronic gastrointestinal infection with parasites, such as Schistosoma japonicum [87] and Strongyloides stercoralis [140].

Despite these observations, the association between microbial invasion of the amniotic cavity (MIAC) and the presence of preeclampsia has not been investigated.

Methods

Study population

A retrospective cohort study was conducted including patients with preeclampsia who met the following inclusion criteria: 1) singleton gestation; 2) gestational age (GA) between 20 and 40 weeks; 3) intact chorioamniotic membranes; and 4) amniocentic fluid available for analysis. Patients were excluded from the study if: 1) spontaneous labor or labor was induced; 2) clinical metadata were unavailable; or 3) a major fetal chromosomal and/or congenital anomaly was present.

All women provided written informed consent prior to the collection of biological samples. The utilization of samples and clinical data for research purposes was approved by the Institutional Review Boards of Sotero del Rio Hospital, Azienda Ospedaliera of Padova, Stanford University, Wayne State University, and the National Institute of Child Health and Human Development (NICHD/NIH/DHHS).

Definitions

Preeclampsia was defined as the new onset of hypertension that developed after 20 weeks of gestation (systolic or diastolic blood pressure ≥140 or ≥90 mm Hg, respectively, measured at two different time points, 4 h–1 week apart) coupled with proteinuria (≥300 mg in a 24-h urine collection, or two random urine specimens obtained 4 h–1 week apart containing ≥1+ by dipstick or one dipstick demonstrating ≥2+ protein) [1, 117]. Severe preeclampsia was defined as systolic blood pressure ≥160 mm Hg or diastolic blood pressure ≥110 mm Hg and/or proteinuria >5 g in a 24-h collection or ≥3+ protein on dipstick, and it was also diagnosed in the presence of multi-organ involvement [1, 117]. HELLP syndrome was defined as hemolysis (serum LDH >600 IU/L; bilirubin >1.2 mg/dL; presence of schistocytes in peripheral blood), elevated liver enzymes (serum ALT and/or AST >70 IU/L) and thrombocytopenia (platelet count <100,000/mm3) [8]. Histological chorioamnionitis was diagnosed based on the presence of inflammatory cells in the chorionic plate and/or chorioamniotic membranes [56, 92]. Acute funisitis was diagnosed by the presence of neutrophils in the wall of the umbilical vessels and/or Wharton’s jelly using criteria previously described [88].

Sampling procedures

Patients with preeclampsia were offered amniocentesis to assess fetal lung maturity in patients close to term. Amniotic fluid (AF) samples were also obtained at the time of cesarean delivery, using meticulous aseptic technique, in a subset of patients. AF was transported in a capped sterile syringe to the clinical laboratory where it was cultured for aerobic and anaerobic bacteria, including genital mycoplasmas, as described [33]. White blood cell (WBC) count [107] and Gram stain [102] of AF were also performed shortly after collection using methods previously described. Shortly after the amniocentesis, AF not required for clinical assessment was centrifuged at 1300×g for 10 min at 4°C, and the supernatant was aliquoted into gamma-irradiated non-pyrogenic DNase/RNase-free cryovials (Corning, Acton, MA, USA), and immediately frozen at −70°C. AF interleukin-6 (IL-6) concentrations were determined using a specific and sensitive immunoassay which had been validated for the analysis of AF as previously described [86]. IL-6 and MMP-8 determinations were performed after all patients were delivered and were not used in clinical management.

Genomic DNA extraction

AF that was not required for clinical purposes (200 μL of each AF sample) was shipped on dry ice to Stanford, CA, where genomic DNA was extracted as described [34]). Extracted DNA was eluted into a final volume of 100 μL of QIAamp® AE buffer and stored at −20°C or colder until thawing for molecular analyses. Strategies to prevent, detect and neutralize potential contamination were implemented at critical steps [12], according to a previously described protocol that included mock extraction blanks to monitor potential contamination (at least one mock per 17 processed samples) [33].

Qualitative analysis by end-point PCR

DNA from each AF sample was analyzed by end-point PCR using broad-range bacterial 16S ribosomal DNA (rDNA) primers, and by group-specific end-point PCR using primers for six taxonomic groups including Candida sp. (Table 1) [14, 31, 63, 89, 141, 145]. PCR reactions, screening of PCR products by gel electrophoresis, and purification and cloning of amplicons from broad-range PCR was performed as described [34]. Sequencing of amplicons directly from group-specific PCR and of recombinant clones from broad-range PCRs (up to 10 clones/reaction) was performed, as described [34].

Table 1
PCR assays used in this study.

Sequence alignment and phylogenetic analysis

Forward and reverse sequence reads were assembled into contigs as described [33]. Assembled sequences from group-specific PCR were queried against the NCBI’s GenBank database using a basic local alignment search tool (BLAST) algorithm [5] to confirm specificity. Assembled sequences from broad-range end-point PCR were aligned and subjected to phylogenetic analysis as described [33]. After removal of vector, human, and poor-quality sequences from the alignment, a neighbor-joining tree was generated based on Felsenstein correction and 682 unambiguous filter positions. Phylotypes were defined using a 99% sequence similarity threshold, which approximates a species-level classification.

Quantitative analysis by real-time PCR

DNA from each sample was analyzed by means of two real-time PCR assays, each of which was designed to amplify in a specific manner and quantify 16S rDNA of domain Bacteria or domain Archaea (Table 1). Reactions were carried out as described [34].

Statistical analysis

Differences in continuous variables between patients with and without MIAC (as determined by either a positive culture or a positive PCR) were computed using the Mann-Whitney U-test. Descriptive statistics were used to report the prevalence of MIAC. A P<0.05 was considered statistically significant. Analysis was performed with SPSS, version 14 (SPSS Inc., Chicago, IL, USA).

Results

Study population

Table 2 displays the demographic and clinical characteristics of the study group. Twenty-eight patients were diagnosed with mild preeclampsia, twenty with severe preeclampsia, nine with superimposed preeclampsia and five with HELLP syndrome. Maternal age, body mass index (BMI), GA at amniocentesis, GA at delivery and birthweight did not differ significantly between patients who tested negative by both PCR and culture and those who tested positive by either method (culture or PCR).

Table 2
Clinical and demographic characteristics of the study population.

Microbial invasion of the amniotic cavity in preeclampsia

Table 3 displays the clinical characteristics of the six patients that were positive by either culture or PCR. The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods. The patient that was positive by culture was negative by PCR, and the five patients that were positive by PCR were negative by culture. Among patients who were negative by both methods (culture and PCR), one had elevated IL-6 and one had elevated MMP-8 AF concentration.

Table 3
Clinical characteristics of six patients with a positive amniotic fluid PCR or culture.

Cultivation methods recovered one species (Ureaplasma urealyticum), whereas molecular methods revealed five phylotypes. Of these five, three were detected by broad-range PCR: Lactobacillus iners (one patient; eight clones; 99.9% identity to type strain CCUG 28746T); Streptococcus sp. (one patient; two clones; 100% identity to Streptococcus anginosus, GenBank AF30688.1) and Corynebacterium tuberculostearicum (one patient; five clones; 99.9% identity to type stain CCUG 45418T). Two phylotypes were detected by group-specific PCR, although the targeted gene and/or size of the amplified sequences limited taxonomic resolution to approximately the genus level: Ureaplasma spp. (two patients) and Sneathia/Leptotrichia (two patients). No members of domain Archaea or genus Candida were detected.

Assessment of the intra-amniotic inflammatory response

Women with MIAC had a median AF IL-6 concentration that was significantly higher than those without MIAC [1.65 ng/mL interquartile range (IQR): 0.35–4.62 vs. 0.22 ng/mL IQR: 0.12–0.51; P=0.002]. There were no significant differences in the rate of positive Gram stain, AF WBC count, and AF concentrations of glucose, and MMP-8 (Table 4).

Table 4
Comparison of intra-amniotic inflammatory response between patients with and without microbial invasion of the amniotic cavity.

Short-term neonatal outcome

In the case with a positive culture for Ureaplasma urealyticum (26.3 weeks of gestation), the neonate was admitted to the neonatal intensive care unit (NICU) and was diagnosed with pneumonia on day 7 of life. The neonate was treated with oxacillin. Of note, Ureaplasma urealyticum was isolated from the nasopharynx on day 20 of life. The neonate developed respiratory distress syndrome (RDS), bronchopulmonary dysplasia, intraventricular hemorrhage grade I, retinopathy of prematurity, and necrotizing enterocolitis. The second preterm neonate (28.9 weeks of gestation; AF positive for Sneathia/Leptotrichia spp. by PCR only) did not have a proven neonatal sepsis. Subsequently, the newborn developed RDS and hyperbilirubinemia. The third preterm neonate (25.1 weeks, AF positive for Corynebacterium tuberculostearicum by PCR only) had RDS, hyperbilirubinemia, patent ductus arteriosus, anemia, thrombocytopenia and renal failure. Although blood cultures were negative, broad-spectrum antibiotics were started immediately after delivery. On day 20 of life, the neonate died of respiratory failure. None of the newborns that were born at term or close to term and were diagnosed with MIAC by PCR required NICU admission or developed short-term complications.

Discussion

Principal findings of the study

1) The rate of MIAC in preeclampsia was 1.6% (1/62) based on cultivation techniques, 8% (5/62) based on PCR, and 9.6% (6/62) based on the combined results of both methods; 2) among the six patients diagnosed with MIAC, three had a positive PCR for Sneathia/Leptotrichia spp.; and 3) patients with preeclampsia and MIAC were more likely to have evidence of an inflammatory response in the amniotic cavity, as determined by a higher median AF IL-6 concentration, than those without MIAC.

Detection of microbial invasion of the amniotic cavity

The AF in normal pregnancy is considered sterile in the majority of cases. However, MIAC has been demonstrated with cultivation techniques in 18% of patients in spontaneous labor at term with intact membranes [106], 34% of women with prelabor rupture of membranes (PROM) at term [104], 13% of women presenting with an episode of preterm labor [46], 32% of women with preterm PROM [46], and 9% of women with a short cervix [50]. Among women with cervical insufficiency, the prevalence of MIAC is about 50% [103]. However, all these estimates are based upon cultivation techniques and rely on the ability to provide adequate conditions required for the growth of microorganisms in the laboratory.

Molecular methods offer a sensitive, cultivation-independent approach for detecting microbes. In particular, broad-range PCR assays that target rDNA allow for detection and characterization of diverse microbial taxa, including unknown species [96]. These methods have been used to assess diversity within the human indigenous microbiota [2, 36] and to characterize microbes associated with a wide range of clinical syndromes [33, 43]. In addition, it is possible to use specific primers that target microorganisms, such as Ureaplasma urealyticum and fungi. Specific assays appear to have a greater sensitivity than “universal” assays for the detection of targeted microorganisms.

Our group has previously reported that specific PCR assays for Ureaplasma urealyticum are more sensitive than cultivation for this species in patients with preterm labor and intact membranes [144], preterm PROM [143] and cervical insufficiency [16]. We have also employed a combination of broad-range and specific PCR assays for bacteria and fungi, and have demonstrated that the combination of culture and molecular methods allows improved detection of MIAC [34]. Indeed, the impetus for including a Sneathia/Leptotrichia spp. group-specific PCR was our prior finding of an unexpectedly high rate of MIAC due to those two related genera [33]. Importantly, an intrauterine inflammatory response is associated with the presence of microbial DNA in the AF, even in the presence of a negative culture [34, 143, 144]. Such findings provide evidence that a positive PCR-based assay has biological significance.

MIAC in patients with preeclampsia

We have not been able to identify any prior study that has systematically examined the presence of MIAC in preeclampsia with either cultivation or molecular methods. The findings reported herein indicate that 9% of women with preeclampsia have MIAC detected with cultivation and molecular techniques. The organisms identified included Ureaplasma urealyticum, Sneathia/Leptotrichia spp., Lactobacillus spp. and Streptococcus spp.

The most common organisms detected in the AF of patients with preeclampsia were Sneathia/Leptotrichia spp. (50% of all MIAC cases) which was identified only by PCR, and Ureaplasma spp. (50%) which was determined by both cultivation techniques (one case) and PCR (two cases). Two of these cases, both detected only by PCR, had normal AF WBC counts, as well as normal AF concentrations of glucose, IL-6 and MMP-8, while the other four cases had at least one abnormal value of intra-amniotic infection/inflammation (IAI) indices.

The taxonomy of the related genera Leptotrichia and Sneathia and our understanding of their potential roles in human disease are still evolving. Both groups are Gram-negative, strictly-anaerobic, fastidious members of the family Fusobacteriaceae [29]. Based on phenotypic and phylogenetic analysis, Collins et al. [24] proposed in 2001 that “Leptotrichia sanguinegens” and three related clinical isolates be assigned to a new genus, Sneathia, as Sneathia sanguinegens gen. nov. sp. nov [24]. Six species of Leptotrichia and one of Sneathia are currently recognized with valid published names.

Leptotrichia sp. are members of the health-associated microbiota of the oropharynx [3]. Sneathia and Leptotrichia have been associated with bacterial vaginosis [80, 124] as well as with other conditions especially in immunosuppressed patients [113, 116]. Sneathia and Leptotrichia are rarely detected during pregnancy. An association with human disease is strongest for four species – L. buccalis, L. trevisanii, L. goodfellowii and S. sanguinegens. Another taxon that has been isolated in culture, “Leptotrichia amnionii” was first described in a case of maternal bacteremia and fetal demise [116].

Sneathia and Leptotrichia are rarely detected as pathogens in association with pregnancy. Indeed, a PubMed search in January 2010 using the key words “Leptotrichia,” and “pregnancy” revealed only nine original reports. This has been attributed to the fastidious nature of these organisms. Hanff et al. [49] reported four cases of postpartum bacteremia due to Sneathia sanguinegens. Subsequently, De Martino et al. [29] reported three cases of maternal postpartum bacteremia with Leptotrichia amnionii or Sneathia sanguinegens, and Boennelycke et al. [11] reported the detection of Leptotrichia amnionii in a blood culture of a patient with septic abortion at 16 weeks of gestation. Gardella et al. [44] identified two cases of Sneathia sanguinegens in culture-negative AF of patients with preterm labor (n=132). Recently, we have reported the results of a large retrospective cohort study in which cultivation methods, as well as broad-range end-point and real-time PCR were used to define the prevalence, diversity and abundance of microbes invading the amniotic cavity in 166 patients with preterm labor. Sneathia sanguinegens and Leptotrichia amnionii were among the taxa detected by PCR only. Four patients had a positive PCR for one or both taxa. Some phylotypes appeared to be as-yet uncultivated and uncharacterized species of Leptotrichia, or to represent a novel sequence type (<94% nearest-neighbor similarity) that clustered with the genus Leptotrichia [34]; this suggests that the diversity of disease-associated Leptotrichia spp. is greater than currently recognized.

In conclusion, we were able to report that the rate of MIAC among patients with preeclampsia is 9.6% using both cultivation and molecular methods. Sneathia/Leptotrichia was detected by PCR in half of the patients with MIAC. Collectively, our findings do not support a prominent role for intra-amniotic infection in the pathophysiology of preeclampsia. The unexpectedly high prevalence of Sneathia/Leptotrichia warrants further investigation.

Acknowledgments

This work was supported, in part, by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, DHHS, and by a grant from the March of Dimes Foundation to DAR. DAR is supported by an NIH Director’s Pioneer Award (NIH DP1OD000964). DAR is supported by the Thomas C. and Joan M. Merigan Endowment at Stanford University. We would like to thank the women who participated in the study. We would also like to thank Elies Bik, Stanford University, for helpful input and assistance during various phases of this study.

Footnotes

The authors stated that there are no conflicts of interest regarding the publication of this article.

References

1. ACOG practice bulletin. Diagnosis and management of preeclampsia and eclampsia. Number 33, January 2002. Obstet Gynecol. 2002;99:159–67. [PubMed]
2. Aas JA, Paster BJ, Stokes LN, Olsen I, Dewhirst FE. Defining the normal bacterial flora of the oral cavity. J Clin Microbiol. 2005;43:5721–32. [PMC free article] [PubMed]
3. Adriaens LM, Alessandri R, Sporri S, Lang NP, Persson GR. Does pregnancy have an impact on the subgingival microbiota? J Periodontol. 2009;80:72–81. [PubMed]
4. Aggarwal PK, Jain V, Sakhuja V, Karumanchi SA, Jha V. Low urinary placental growth factor is a marker of preeclampsia. Kidney Int. 2006;69:621–4. [PubMed]
5. Altschul SF, Gish W, Miller W, Myers EW, Lipman DJ. Basic local alignment search tool. J Mol Biol. 1990;215:403–10. [PubMed]
6. Arriaga-Pizano L, Jimenez-Zamudio L, Vadillo-Ortega F, Martinez-Flores A, Herrerias-Canedo T, Hernandez-Guerrero C. The predominant Th1 cytokine profile in maternal plasma of preeclamptic women is not reflected in the choriodecidual and fetal compartments. J Soc Gynecol Investig. 2005;12:335–42. [PubMed]
7. Barden A, Graham D, Beilin LJ, Ritchie J, Baker R, Walters BN, et al. Neutrophil CD11B expression and neutrophil activation in preeclampsia. Clin Sci (Lond) 1997;92:37–44. [PubMed]
8. Barton JR, Sibai BM. Diagnosis and management of hemolysis, elevated liver enzymes, and low platelets syndrome. Clin Perinatol. 2004;31:807–33. vii. [PubMed]
9. Beck JD, Pankow J, Tyroler HA, Offenbacher S. Dental infections and atherosclerosis. Am Heart J. 1999;138:S528–33. [PubMed]
10. Benyo DF, Smarason A, Redman CW, Sims C, Conrad KP. Expression of inflammatory cytokines in placentas from women with preeclampsia. J Clin Endocrinol Metab. 2001;86:2505–12. [PubMed]
11. Boennelycke M, Christensen JJ, Arpi M, Krause S. Leptotrichia amnionii found in septic abortion in Denmark. Scand J Infect Dis. 2007;39:382–3. [PubMed]
12. Borst A, Box AT, Fluit AC. False-positive results and contamination in nucleic acid amplification assays: suggestions for a prevent and destroy strategy. Eur J Clin Microbiol Infect Dis. 2004;23:289–99. [PubMed]
13. Bretelle F, Sabatier F, Blann A, D’Ercole C, Boutiere B, Mutin M, et al. Maternal endothelial soluble cell adhesion molecules with isolated small for gestational age fetuses: comparison with preeclampsia. Br J Obstet Gynaecol. 2001;108:1277–82. [PubMed]
14. Brinig MM, Lepp PW, Ouverney CC, Armitage GC, Relman DA. Prevalence of bacteria of division TM7 in human sub-gingival plaque and their association with disease. Appl Environ Microbiol. 2003;69:1687–94. [PMC free article] [PubMed]
15. Brosens IA, Robertson WB, Dixon HG. The role of the spiral arteries in the pathogenesis of preeclampsia. Obstet Gynecol Annu. 1972;1:177–91. [PubMed]
16. Bujold E, Morency AM, Rallu F, Ferland S, Tetu A, Duperron L, et al. Bacteriology of amniotic fluid in women with suspected cervical insufficiency. J Obstet Gynaecol Can. 2008;30:882–7. [PubMed]
17. Bujold E, Romero R, Chaiworapongsa T, Kim YM, Kim GJ, Kim MR, et al. Evidence supporting that the excess of the sVEGFR-1 concentration in maternal plasma in preeclampsia has a uterine origin. J Matern Fetal Neonatal Med. 2005;18:9–16. [PubMed]
18. Chaiworapongsa T, Gervasi MT, Refuerzo J, Espinoza J, Yoshimatsu J, Berman S, et al. Maternal lymphocyte sub-populations (CD45RA+ and CD45RO+) in preeclampsia. Am J Obstet Gynecol. 2002;187:889–93. [PubMed]
19. Chaiworapongsa T, Romero R, Espinoza J, Bujold E, Mee KY, Goncalves LF, et al. Evidence supporting a role for blockade of the vascular endothelial growth factor system in the pathophysiology of preeclampsia. Young Investigator Award. Am J Obstet Gynecol. 2004;190:1541–7. [PubMed]
20. Chaiworapongsa T, Romero R, Gotsch F, Espinoza J, Nien JK, Goncalves L, et al. Low maternal concentrations of soluble vascular endothelial growth factor receptor-2 in preeclampsia and small for gestational age. J Matern Fetal Neonatal Med. 2008;21:41–52. [PubMed]
21. Chaiworapongsa T, Romero R, Kim YM, Kim GJ, Kim MR, Espinoza J, et al. Plasma soluble vascular endothelial growth factor receptor-1 concentration is elevated prior to the clinical diagnosis of preeclampsia. J Matern Fetal Neonatal Med. 2005;17:3–18. [PubMed]
22. Chen LJ, Gao H, Zhou H, Zou L, Zou P. Contribution of interferon-gamma receptor 1 gene polymorphisms to preeclampsia in China. Am J Reprod Immunol. 2010;63:331–8. [PubMed]
23. Clark BA, Halvorson L, Sachs B, Epstein FH. Plasma endothelin levels in preeclampsia: elevation and correlation with uric acid levels and renal impairment. Am J Obstet Gynecol. 1992;166:962–8. [PubMed]
24. Collins MD, Hoyles L, Tornqvist E, von Essen R, Falsen E. Characterization of some strains from human clinical sources which resemble “Leptotrichia sanguinegens”: description of Sneathia sanguinegens sp. nov., gen. nov. Syst Appl Microbiol. 2001;24:358–61. [PubMed]
25. Conrad KP, Miles TM, Benyo DF. Circulating levels of immunoreactive cytokines in women with preeclampsia. Am J Reprod Immunol. 1998;40:102–11. [PubMed]
26. Crispi F, Dominguez C, Llurba E, Martin-Gallan P, Cabero L, Gratacos E. Placental angiogenic growth factors and uterine artery Doppler findings for characterization of different subsets in preeclampsia and in isolated intrauterine growth restriction. Am J Obstet Gynecol. 2006;195:201–7. [PubMed]
27. Daniel Y, Kupferminc MJ, Baram A, Jaffa AJ, Fait G, Wolman I, et al. Plasma interleukin-12 is elevated in patients with preeclampsia. Am J Reprod Immunol. 1998;39:376–80. [PubMed]
28. Davidge ST. Oxidative stress and altered endothelial cell function in preeclampsia. Semin Reprod Endocrinol. 1998;16:65–73. [PubMed]
29. De Martino SJ, Mahoudeau I, Brettes JP, Piemont Y, Monteil H, Jaulhac B. Peripartum bacteremias due to Leptotrichia amnionii and Sneathia sanguinegens, rare causes of fever during and after delivery. J Clin Microbiol. 2004;42:5940–3. [PMC free article] [PubMed]
30. Dekker GA, Sibai BM. Etiology and pathogenesis of preeclampsia: current concepts. Am J Obstet Gynecol. 1998;179:1359–75. [PubMed]
31. DeLong EF. Archaea in coastal marine environments. Proc Natl Acad Sci USA. 1992;89:5685–9. [PMC free article] [PubMed]
32. Di Renzo GC. The great obstetrical syndromes. J Matern Fetal Neonatal Med. 2009;22:633–5. [PubMed]
33. DiGiulio DB, Romero R, Amogan HP, Kusanovic JP, Bik EM, Gotsch F, et al. Microbial prevalence, diversity and abundance in amniotic fluid during preterm labor: a molecular and culture-based investigation. PLoS One. 2008;3:e3056. [PMC free article] [PubMed]
34. DiGiulio DB, Romero R, Kusanovic JP, Gomez R, Kim CJ, Seok K, et al. Prevalence and diversity of microbes in the amniotic fluid, the fetal inflammatory response, and fetal outcome in women with preterm prelabor rupture of membranes. Am J Reprod Immunol. 2010 [PMC free article] [PubMed]
35. Dudley DJ, Hunter C, Mitchell MD, Varner MW, Gately M. Elevations of serum interleukin-12 concentrations in women with severe preeclampsia and HELLP syndrome. J Reprod Immunol. 1996;31:97–107. [PubMed]
36. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, et al. Diversity of the human intestinal microbial flora. Science. 2005;308:1635–8. [PMC free article] [PubMed]
37. Erez O, Romero R, Espinoza J, Fu W, Todem D, Kusanovic JP, et al. The change in concentrations of angiogenic and anti-angiogenic factors in maternal plasma between the first and second trimesters in risk assessment for the subsequent development of preeclampsia and small-for-gestational age. J Matern Fetal Neonatal Med. 2008;21:279–87. [PMC free article] [PubMed]
38. Espinoza J, Nien JK, Kusanovic JP, Goncalves LF, Medina LH, Gomez R, et al. The combined use of uterine artery Doppler and maternal plasma placental growth factor concentrations identifies patients at risk for early onset and/or severe preeclampsia. Ultrasound Obstet Gynecol. 2006;28:387–8. [PMC free article] [PubMed]
39. Espinoza J, Romero R, Mee KY, Kusanovic JP, Hassan S, Erez O, et al. Normal and abnormal transformation of the spiral arteries during pregnancy. J Perinat Med. 2006;34:447–58. [PubMed]
40. Espinoza J, Romero R, Nien JK, Kusanovic JP, Richani K, Gomez R, et al. A role of the anti-angiogenic factor s-VEGFR-1 in the ‘mirror syndrome’ (Ballantyne’s syndrome) J Matern Fetal Neonatal Med. 2006;19:607–13. [PubMed]
41. Faas MM, Broekema M, Moes H, van der SG, Heineman MJ, de Vos P. Altered monocyte function in experimental preeclampsia in the rat. Am J Obstet Gynecol. 2004;191:1192–8. [PubMed]
42. Faas MM, Schuiling GA, Baller JF, Visscher CA, Bakker WW. A new animal model for human preeclampsia: ultra-low-dose endotoxin infusion in pregnant rats. Am J Obstet Gynecol. 1994;171:158–64. [PubMed]
43. Fredricks DN, Fiedler TL, Marrazzo JM. Molecular identification of bacteria associated with bacterial vaginosis. N Engl J Med. 2005;353:1899–911. [PubMed]
44. Gardella C, Riley DE, Hitti J, Agnew K, Krieger JN, Eschenbach D. Identification and sequencing of bacterial rDNAs in culture-negative amniotic fluid from women in premature labor. Am J Perinatol. 2004;21:319–23. [PubMed]
45. Gervasi MT, Chaiworapongsa T, Pacora P, Naccasha N, Yoon BH, Maymon E, et al. Phenotypic and metabolic characteristics of monocytes and granulocytes in preeclampsia. Am J Obstet Gynecol. 2001;185:792–7. [PubMed]
46. Goncalves LF, Chaiworapongsa T, Romero R. Intrauterine infection and prematurity. Ment Retard Dev Disabil Res Rev. 2002;8:3–13. [PubMed]
47. Gotsch F, Romero R, Kusanovic JP, Chaiworapongsa T, Dombrowski M, Erez O, et al. Preeclampsia and small-for-gestational age are associated with decreased concentrations of a factor involved in angiogenesis: soluble Tie-2. J Matern Fetal Neonatal Med. 2008;21:389–402. [PMC free article] [PubMed]
48. Haller H, Ziegler EM, Homuth V, Drab M, Eichhorn J, Nagy Z, et al. Endothelial adhesion molecules and leukocyte integrins in preeclamptic patients. Hypertension. 1997;29:291–6. [PubMed]
49. Hanff PA, Rosol-Donoghue JA, Spiegel CA, Wilson KH, Moore LH. Leptotrichia sanguinegens sp. nov., a new agent of postpartum and neonatal bacteremia. Clin Infect Dis. 1995;20(Suppl 2):S237–9. [PubMed]
50. Hassan S, Romero R, Hendler I, Gomez R, Khalek N, Espinoza J, et al. A sonographic short cervix as the only clinical manifestation of intra-amniotic infection. J Perinat Med. 2006;34:13–9. [PMC free article] [PubMed]
51. Higgins JR, Papayianni A, Brady HR, Darling MR, Walshe JJ. Circulating vascular cell adhesion molecule-1 in preeclampsia, gestational hypertension, and normal pregnancy: evidence of selective dysregulation of vascular cell adhesion molecule-1 homeostasis in preeclampsia. Am J Obstet Gynecol. 1998;179:464–9. [PubMed]
52. Hnat MD, Meadows JW, Brockman DE, Pitzer B, Lyall F, Myatt L. Heat shock protein-70 and 4-hydroxy-2-nonenal adducts in human placental villous tissue of normotensive, preeclamptic and intrauterine growth restricted pregnancies. Am J Obstet Gynecol. 2005;193:836–40. [PubMed]
53. Kanayama N, She L, Maehara K, Kajiwara Y, Terao T. Induction of HELLP syndrome-like biochemical parameters by stimulation of the celiac ganglion in rats. J Hypertens. 1996;14:453–9. [PubMed]
54. Ke D, Menard C, Picard FJ, Boissinot M, Ouellette M, Roy PH, et al. Development of conventional and real-time PCR assays for the rapid detection of group B streptococci. Clin Chem. 2000;46:324–31. [PubMed]
55. Khong TY, De Wolf F, Robertson WB, Brosens I. Inadequate maternal vascular response to placentation in pregnancies complicated by preeclampsia and by small-for-gestational age infants. Br J Obstet Gynaecol. 1986;93:1049–59. [PubMed]
56. Kim MJ, Romero R, Gervasi MT, Kim JS, Yoo W, Lee DC, et al. Widespread microbial invasion of the chorioamniotic membranes is a consequence and not a cause of intra-amniotic infection. Lab Invest. 2009;89:924–36. [PMC free article] [PubMed]
57. Koga K, Osuga Y, Yoshino O, Hirota Y, Ruimeng X, Hirata T, et al. Elevated serum soluble vascular endothelial growth factor receptor 1 (sVEGFR-1) levels in women with preeclampsia. J Clin Endocrinol Metab. 2003;88:2348–51. [PubMed]
58. Kraayenbrink AA, Dekker GA, van Kamp GJ, van Geijn HP. Endothelial vasoactive mediators in preeclampsia. Am J Obstet Gynecol. 1993;169:160–5. [PubMed]
59. Krauss T, Pauer HU, Augustin HG. Prospective analysis of placenta growth factor (PlGF) concentrations in the plasma of women with normal pregnancy and pregnancies complicated by preeclampsia. Hypertens Pregnancy. 2004;23:101–11. [PubMed]
60. Kupferminc MJ, Daniel Y, Englender T, Baram A, Many A, Jaffa AJ, et al. Vascular endothelial growth factor is increased in patients with preeclampsia. Am J Reprod Immunol. 1997;38:302–6. [PubMed]
61. Kusanovic JP, Romero R, Chaiworapongsa T, Erez O, Mittal P, Vaisbuch E, et al. A prospective cohort study of the value of maternal plasma concentrations of angiogenic and anti-angiogenic factors in early pregnancy and midtrimester in the identification of patients destined to develop preeclampsia. J Matern Fetal Neonatal Med. 2009;22:1021–38. [PMC free article] [PubMed]
62. Kusanovic JP, Romero R, Hassan SS, Gotsch F, Edwin S, Chaiworapongsa T, et al. Maternal serum soluble CD30 is increased in normal pregnancy, but decreased in preeclampsia and small for gestational age pregnancies. J Matern Fetal Neonatal Med. 2007;20:867–78. [PMC free article] [PubMed]
63. Lepp PW, Brinig MM, Ouverney CC, Palm K, Armitage GC, Relman DA. Methanogenic archaea and human periodontal disease. Proc Natl Acad Sci USA. 2004;101:6176–81. [PMC free article] [PubMed]
64. Levine RJ, Karumanchi SA. Circulating angiogenic factors in preeclampsia. Clin Obstet Gynecol. 2005;48:372–86. [PubMed]
65. Levine RJ, Lam C, Qian C, Yu KF, Maynard SE, Sachs BP, et al. Soluble endoglin and other circulating antiangiogenic factors in preeclampsia. N Engl J Med. 2006;355:992–1005. [PubMed]
66. Levine RJ, Maynard SE, Qian C, Lim KH, England LJ, Yu KF, et al. Circulating angiogenic factors and the risk of preeclampsia. N Engl J Med. 2004;350:672–83. [PubMed]
67. Levine RJ, Qian C, Maynard SE, Yu KF, Epstein FH, Karumanchi SA. Serum sFlt1 concentration during preeclampsia and mid trimester blood pressure in healthy nulliparous women. Am J Obstet Gynecol. 2006;194:1034–41. [PubMed]
68. Levine RJ, Thadhani R, Qian C, Lam C, Lim KH, Yu KF, et al. Urinary placental growth factor and risk of preeclampsia. J Am Med Assoc. 2005;293:77–85. [PubMed]
69. Lindheimer MD. Hypertension in pregnancy. Hypertension. 1993;22:127–37. [PubMed]
70. Lindheimer MD, Romero R. Emerging roles of antiangiogenic and angiogenic proteins in pathogenesis and prediction of preeclampsia. Hypertension. 2007;50:35–6. [PubMed]
71. Liu LP, Huang W, Lu YC, Liao AH. Enhanced maternal anti-fetal immunity contributes to the severity of hypertensive disorder complicating pregnancy. Am J Reprod Immunol. 2010 [Epub ahead of print] [PubMed]
72. Lok CA, Jebbink J, Nieuwland R, Faas MM, Boer K, Sturk A, et al. Leukocyte activation and circulating leukocyte-derived microparticles in preeclampsia. Am J Reprod Immunol. 2009;61:346–59. [PubMed]
73. Lyall F, Greer IA, Boswell F, Fleming R. Suppression of serum vascular endothelial growth factor immunoreactivity in normal pregnancy and in preeclampsia. Br J Obstet Gynaecol. 1997;104:223–8. [PubMed]
74. MacKay AP, Berg CJ, Atrash HK. Pregnancy-related mortality from preeclampsia and eclampsia. Obstet Gynecol. 2001;97:533–8. [PubMed]
75. Maynard SE, Min JY, Merchan J, Lim KH, Li J, Mondal S, et al. Excess placental soluble fms-like tyrosine kinase 1 (sFlt1) may contribute to endothelial dysfunction, hypertension, and proteinuria in preeclampsia. J Clin Invest. 2003;111:649–58. [PMC free article] [PubMed]
76. Mazaki-Tovi S, Romero R, Kim SK, Vaisbuch E, Kusanovic JP, Erez O, et al. Could alterations in maternal plasma visfatin concentration participate in the phenotype definition of preeclampsia and SGA? J Matern Fetal Neonatal Med. 2009 [PMC free article] [PubMed]
77. Mazaki-Tovi S, Romero R, Vaisbuch E, Kusanovic JP, Erez O, Gotsch F, et al. Maternal serum adiponectin multimers in preeclampsia. J Perinat Med. 2009;37:349–63. [PMC free article] [PubMed]
78. McKeeman GC, Ardill JE, Caldwell CM, Hunter AJ, McClure N. Soluble vascular endothelial growth factor receptor-1 (sFlt-1) is increased throughout gestation in patients who have preeclampsia develop. Am J Obstet Gynecol. 2004;191:1240–6. [PubMed]
79. Meekins JW, McLaughlin PJ, West DC, McFadyen IR, Johnson PM. Endothelial cell activation by tumour necrosis factor-alpha (TNF-alpha) and the development of preeclampsia. Clin Exp Immunol. 1994;98:110–4. [PMC free article] [PubMed]
80. Mitchell CM, Hitti JE, Agnew KJ, Fredricks DN. Comparison of oral and vaginal metronidazole for treatment of bacterial vaginosis in pregnancy: impact on fastidious bacteria. BMC Infect Dis. 2009;9:89. [PMC free article] [PubMed]
81. Mittendorf R, Lain KY, Williams MA, Walker CK. Preeclampsia. A nested, case-control study of risk factors and their interactions. J Reprod Med. 1996;41:491–6. [PubMed]
82. Myatt L, Cui X. Oxidative stress in the placenta. Histochem Cell Biol. 2004;122:369–82. [PubMed]
83. Myatt L, Eis AL, Brockman DE, Kossenjans W, Greer IA, Lyall F. Differential localization of superoxide dismutase isoforms in placental villous tissue of normotensive, preeclamptic, and intrauterine growth-restricted pregnancies. J Histochem Cytochem. 1997;45:1433–8. [PubMed]
84. Ness RB, Sibai BM. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia. Am J Obstet Gynecol. 2006;195:40–9. [PubMed]
85. Newman MG, Robichaux AG, Stedman CM, Jaekle RK, Fontenot MT, Dotson T, et al. Perinatal outcomes in preeclampsia that is complicated by massive proteinuria. Am J Obstet Gynecol. 2003;188:264–8. [PubMed]
86. Nien JK, Yoon BH, Espinoza J, Kusanovic JP, Erez O, Soto E, et al. A rapid MMP-8 bedside test for the detection of intra-amniotic inflammation identifies patients at risk for imminent preterm delivery. Am J Obstet Gynecol. 2006;195:1025–30. [PubMed]
87. Obata NH, Kurauchi O, Kikkawa F, Yamada M, Fukuda Y, Itakura A. Preeclampsia with fetal death in a patient with schistosomiasis japonica. Arch Gynecol Obstet. 1998;261:101–4. [PubMed]
88. Pacora P, Chaiworapongsa T, Maymon E, Kim YM, Gomez R, Yoon BH, et al. Funisitis and chorionic vasculitis: the histological counterpart of the fetal inflammatory response syndrome. J Matern Fetal Neonatal Med. 2002;11:18–25. [PubMed]
89. Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. Development of the human infant intestinal microbiota. PLoS Biol. 2007;5:e177. [PMC free article] [PubMed]
90. Poston L, Chappell LC. Is oxidative stress involved in the aetiology of preeclampsia? Acta Paediatr Suppl. 2001;90:3–5. [PubMed]
91. Rajakumar A, Michael HM, Rajakumar PA, Shibata E, Hubel CA, Karumanchi SA, et al. Extra-placental expression of vascular endothelial growth factor receptor-1, (Flt-1) and soluble Flt-1 (sFlt-1), by peripheral blood mononuclear cells (PBMCs) in normotensive and preeclamptic pregnant women. Placenta. 2005;26:563–73. [PubMed]
92. Redline RW, Faye-Petersen O, Heller D, Qureshi F, Savell V, Vogler C. Amniotic infection syndrome: nosology and reproducibility of placental reaction patterns. Pediatr Dev Pathol. 2003;6:435–48. [PubMed]
93. Redman CW, Sacks GP, Sargent IL. Preeclampsia: an excessive maternal inflammatory response to pregnancy. Am J Obstet Gynecol. 1999;180:499–506. [PubMed]
94. Redman CW, Sargent IL. Placental debris, oxidative stress and preeclampsia. Placenta. 2000;21:597–602. [PubMed]
95. Redman CW, Sargent IL. Latest advances in understanding preeclampsia. Science. 2005;308:1592–4. [PubMed]
96. Relman D, Loutit J, Schmidt T, Falkow S, Tompkins L. The agent of bacillary angiomatosis: an approach to the identification of uncultured pathogens. N Engl J Med. 1990;323:1573–80. [PubMed]
97. Rizzo R, Andersen AS, Lassen MR, Sorensen HC, Bergholt T, Larsen MH, et al. Soluble human leukocyte antigen-G isoforms in maternal plasma in early and late pregnancy. Am J Reprod Immunol. 2009;62:320–38. [PubMed]
98. Roberts JM, Taylor RN, Musci TJ, Rodgers GM, Hubel CA, McLaughlin MK. Preeclampsia: an endothelial cell disorder. Am J Obstet Gynecol. 1989;161:1200–4. [PubMed]
99. Robinson CJ, Johnson DD, Chang EY, Armstrong DM, Wang W. Evaluation of placenta growth factor and soluble Fms-like tyrosine kinase 1 receptor levels in mild and severe preeclampsia. Am J Obstet Gynecol. 2006;195:255–9. [PubMed]
100. Romero R. The child is the father of the man. Prenat Neonat Med. 1996;1:8–11.
101. Romero R. Prenatal medicine: the child is the father of the man. 1996. J Matern Fetal Neonatal Med. 2009;22:636–9. [PubMed]
102. Romero R, Emamian M, Quintero R, Wan M, Hobbins JC, Mazor M, et al. The value and limitations of the Gram stain examination in the diagnosis of intraamniotic infection. Am J Obstet Gynecol. 1988;159:114–9. [PubMed]
103. Romero R, Gonzalez R, Sepulveda W, Brandt F, Ramirez M, Sorokin Y, et al. Infection and labor. VIII. Microbial invasion of the amniotic cavity in patients with suspected cervical incompetence: prevalence and clinical significance. Am J Obstet Gynecol. 1992;167:1086–91. [PubMed]
104. Romero R, Mazor M, Morretti R, Avila C, Oyarzun E, Insunza A, et al. Infection and labor. VII: Microbial invasion of the amniotic cavity in spontaneous rupture of membranes at term. Am J Obstet Gynecol. 1992;166:129–133. [PubMed]
105. Romero R, Nien JK, Espinoza J, Todem D, Fu W, Chung H, et al. A longitudinal study of angiogenic (placental growth factor) and anti-angiogenic (soluble endoglin and soluble vascular endothelial growth factor receptor-1) factors in normal pregnancy and patients destined to develop preeclampsia and deliver a small for gestational age neonate. J Matern Fetal Neonatal Med. 2008;21:9–23. [PMC free article] [PubMed]
106. Romero R, Nores J, Mazor M, Sepulveda W, Oyarzun E, Parra M, et al. Microbial invasion of the amniotic cavity during term labor. Prevalence and clinical significance. J Reprod Med. 1993;38:543–8. [PubMed]
107. Romero R, Quintero R, Nores J, Avila C, Mazor M, Hanaoka S, et al. Amniotic fluid white blood cell count: a rapid and simple test to diagnose microbial invasion of the amniotic cavity and predict preterm delivery. Am J Obstet Gynecol. 1991;165:821–30. [PubMed]
108. Roy KK, Malhotra N, Banerjee K. Recurrent eclampsia in a woman with chronic pyelonephritis. Eur J Obstet Gynecol Reprod Biol. 2001;94:307–8. [PubMed]
109. Sacks GP, Studena K, Sargent K, Redman CW. Normal pregnancy and preeclampsia both produce inflammatory changes in peripheral blood leukocytes akin to those of sepsis. Am J Obstet Gynecol. 1998;179:80–6. [PubMed]
110. Saito S, Umekage H, Sakamoto Y, Sakai M, Tanebe K, Sasaki Y, et al. Increased T-helper-1-type immunity and decreased T-helper-2-type immunity in patients with preeclampsia. Am J Reprod Immunol. 1999;41:297–306. [PubMed]
111. Sakawi Y, Tarpey M, Chen YF, Calhoun DA, Connor MG, Chestnut DH, et al. Evaluation of low-dose endotoxin administration during pregnancy as a model of preeclampsia. Anesthesiology. 2000;93:1446–55. [PubMed]
112. Schiff E, Ben-Baruch G, Peleg E, Rosenthal T, Alcalay M, Devir M, et al. Immunoreactive circulating endothelin-1 in normal and hypertensive pregnancies. Am J Obstet Gynecol. 1992;166:624–8. [PubMed]
113. Schwartz DN, Schable B, Tenover FC, Miller RA. Leptotrichia buccalis bacteremia in patients treated in a single bone marrow transplant unit. Clin Infect Dis. 1995;20:762–7. [PubMed]
114. Seely EW. Hypertension in pregnancy: a potential window into long-term cardiovascular risk in women. J Clin Endocrinol Metab. 1999;84:1858–61. [PubMed]
115. Shibata E, Rajakumar A, Powers RW, Larkin RW, Gilmour C, Bodnar LM, et al. Soluble fms-like tyrosine kinase 1 is increased in preeclampsia but not in normotensive pregnancies with small-for-gestational-age neonates: relationship to circulating placental growth factor. J Clin Endocrinol Metab. 2005;90:4895–903. [PubMed]
116. Shukla SK, Meier PR, Mitchell PD, Frank DN, Reed KD. Leptotrichia amnionii sp. nov., a novel bacterium isolated from the amniotic fluid of a woman after intrauterine fetal demise. J Clin Microbiol. 2002;40:3346–9. [PMC free article] [PubMed]
117. Sibai B, Dekker G, Kupferminc M. Preeclampsia. Lancet. 2005;365:785–99. [PubMed]
118. Sibai BM, Gordon T, Thom E, Caritis SN, Klebanoff M, McNellis D, et al. Risk factors for preeclampsia in healthy nulliparous women: a prospective multicenter study. The National Institute of Child Health and Human Development Network of Maternal-Fetal Medicine Units. Am J Obstet Gynecol. 1995;172:642–8. [PubMed]
119. Singh A, Sharma D, Raghunandan C, Bhattacharjee J. Role of inflammatory cytokines and eNOS gene polymorphism in pathophysiology of preeclampsia. Am J Reprod Immunol. 2010;63:244–51. [PubMed]
120. Soto E, Romero R, Richani K, Espinoza J, Chaiworapongsa T, Nien JK, et al. Preeclampsia and pregnancies with small-for-gestational age neonates have different profiles of complement split products. J Matern Fetal Neonatal Med. 2009 [Epub ahead of print] [PMC free article] [PubMed]
121. Staff AC, Braekke K, Harsem NK, Lyberg T, Holthe MR. Circulating concentrations of sFlt1 (soluble fms-like tyrosine kinase 1) in fetal and maternal serum during preeclampsia. Eur J Obstet Gynecol Reprod Biol. 2005;122:33–9. [PubMed]
122. Stepan H, Faber R. Elevated sFlt1 level and preeclampsia with parvovirus-induced hydrops. N Engl J Med. 2006;354:1857–8. [PubMed]
123. Sunder-Plassmann G, Derfler K, Wagner L, Stockenhuber F, Endler M, Nowotny C, et al. Increased serum activity of interleukin-2 in patients with preeclampsia. J Autoimmun. 1989;2:203–5. [PubMed]
124. Tamrakar R, Yamada T, Furuta I, Cho K, Morikawa M, Yamada H, et al. Association between Lactobacillus species and bacterial vaginosis-related bacteria, and bacterial vaginosis scores in pregnant Japanese women. BMC Infect Dis. 2007;7:128. [PMC free article] [PubMed]
125. Taylor RN, de Groot CJ, Cho YK, Lim KH. Circulating factors as markers and mediators of endothelial cell dysfunction in preeclampsia. Semin Reprod Endocrinol. 1998;16:17–31. [PubMed]
126. Teran E, Escudero C, Moya W, Flores M, Vallance P, Lopez-Jaramillo P. Elevated C-reactive protein and pro-inflammatory cytokines in Andean women with preeclampsia. Int J Gynaecol Obstet. 2001;75:243–9. [PubMed]
127. Thadhani R, Mutter WP, Wolf M, Levine RJ, Taylor RN, Sukhatme VP, et al. First trimester placental growth factor and soluble fms-like tyrosine kinase 1 and risk for preeclampsia. J Clin Endocrinol Metab. 2004;89:770–5. [PubMed]
128. Than NG, Erez O, Wildman DE, Tarca AL, Edwin SS, Abbas A, et al. Severe preeclampsia is characterized by increased placental expression of galectin-1. J Matern Fetal Neonatal Med. 2008;21:429–42. [PMC free article] [PubMed]
129. Than NG, Romero R, Erez O, Kusanovic JP, Tarca AL, Edwin SS, et al. A role for mannose-binding lectin, a component of the innate immune system in preeclampsia. Am J Reprod Immunol. 2008;60:333–45. [PMC free article] [PubMed]
130. Tidwell SC, Ho HN, Chiu WH, Torry RJ, Torry DS. Low maternal serum levels of placenta growth factor as an antecedent of clinical preeclampsia. Am J Obstet Gynecol. 2001;184:1267–72. [PubMed]
131. Toft JH, Lian IA, Tarca AL, Erez O, Espinoza J, Eide IP, et al. Whole-genome microarray and targeted analysis of angiogenesis-regulating gene expression (ENG, FLT1, VEGF, PlGF) in placentas from preeclamptic and small-for-gestational-age pregnancies. J Matern Fetal Neonatal Med. 2008;21:267–73. [PubMed]
132. Torry DS, Wang HS, Wang TH, Caudle MR, Torry RJ. Preeclampsia is associated with reduced serum levels of placenta growth factor. Am J Obstet Gynecol. 1998;179:1539–44. [PubMed]
133. Tsatsaris V, Goffin F, Munaut C, Brichant JF, Pignon MR, Noel A, et al. Overexpression of the soluble vascular endothelial growth factor receptor in preeclamptic patients: pathophysiological consequences. J Clin Endocrinol Metab. 2003;88:5555–63. [PubMed]
134. Vaisbuch E, Romero R, Mazaki-Tovi S, Erez O, Kim SK, Chaiworapongsa T, et al. Retinol binding protein 4 – a novel association with early-onset preeclampsia. J Perinat Med. 2010;38:129–39. [PMC free article] [PubMed]
135. Venkatesha S, Toporsian M, Lam C, Hanai J, Mammoto T, Kim YM, et al. Soluble endoglin contributes to the pathogenesis of preeclampsia. Nat Med. 2006;12:642–9. [PubMed]
136. Villar J, Carroli G, Wojdyla D, Abalos E, Giordano D, Ba’aqeel H, et al. Preeclampsia, gestational hypertension and intrauterine growth restriction, related or independent conditions? Am J Obstet Gynecol. 2006;194:921–31. [PubMed]
137. Vince GS, Starkey PM, Austgulen R, Kwiatkowski D, Redman CW. Interleukin-6, tumour necrosis factor and soluble tumour necrosis factor receptors in women with preeclampsia. Br J Obstet Gynaecol. 1995;102:20–5. [PubMed]
138. Wang Y, Walsh SW. Placental mitochondria as a source of oxidative stress in preeclampsia. Placenta. 1998;19:581–6. [PubMed]
139. Williams MA, Farrand A, Mittendorf R, Sorensen TK, Zingheim RW, O’Reilly GC, et al. Maternal second trimester serum tumor necrosis factor-alpha-soluble receptor p55 (sTNFp55) and subsequent risk of preeclampsia. Am J Epidemiol. 1999;149:323–9. [PubMed]
140. Wilson J, Walthert SE, Gillett WR. Strongyloides stercoralis and severe preeclampsia. NZ Med J. 1998;111:83. [PubMed]
141. Wilson KH, Blitchington R, Frothingham R, Wilson JA. Phylogeny of the Whipple’s-disease-associated bacterium. Lancet. 1991;338:474–5. [PubMed]
142. Xie F, Turvey SE, Williams MA, Mor G, von Dadelszen P. Toll-like receptor signaling and preeclampsia. Am J Reprod Immunol. 2010;63:7–16. [PubMed]
143. Yoon BH, Romero R, Kim M, Kim EC, Kim T, Park JS, et al. Clinical implications of detection of ureaplasma urealyticum in the amniotic cavity with the polymerase chain reaction. Am J Obstet Gynecol. 2000;183:1130–7. [PubMed]
144. Yoon BH, Romero R, Lim JH, Shim SS, Hong JS, Shim JY, et al. The clinical significance of detecting ureaplasma urealyticum by the polymerase chain reaction in the amniotic fluid of patients with preterm labor. Am J Obstet Gynecol. 2003;189:919–24. [PubMed]
145. Zariffard MR, Saifuddin M, Sha BE, Spear GT. Detection of bacterial vaginosis-related organisms by real-time PCR for Lactobacilli, Gardnerella vaginalis and Mycoplasma hominis. FEMS Immunol Med Microbiol. 2002;34:277–81. [PubMed]
146. Zhou Y, McMaster M, Woo K, Janatpour M, Perry J, Karpanen T, et al. Vascular endothelial growth factor ligands and receptors that regulate human cytotrophoblast survival are dysregulated in severe preeclampsia and hemolysis, elevated liver enzymes, and low platelets syndrome. Am J Pathol. 2002;160:1405–23. [PMC free article] [PubMed]
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